30 June 2010. Theories about the neurobiology underlying cognitive deficits in schizophrenia lead to inaccurate predictions about working memory impairments in the disorder, says a study in the June Archives of General Psychiatry. James Gold of the University of Maryland School of Medicine in Baltimore and colleagues questioned whether, as some theories suggest, working memory would be unstable and imprecise in schizophrenia. Using novel methods that enabled them to tease apart different aspects of working memory, they found no evidence that people with schizophrenia have more fleeting or off-the-mark memories than healthy subjects. Rather, they are unable to simultaneously hold as many items at once in working memory. In light of these findings, Gold et al. recommend a trip back to the drawing board to revise current theories of the neurobiology of working memory deficits in schizophrenia.

Schizophrenia-related cognitive deficits hamper patients’ lives (see Green, 1996), and a recent meta-analysis found consistent evidence of large working memory deficits in subjects with schizophrenia as compared to healthy subjects (Forbes et al., 2009). Working memory, the ability to briefly store and manipulate information, guides goal-directed behavior through other cognitive processes.

Several researchers have tried to explain the biological basis of cognitive symptoms in schizophrenia. For instance, John Lisman and colleagues (Lisman et al., 2008) suggest that reduced N-methyl-D-aspartate (NMDA) channel function impairs memory in schizophrenia by disinhibiting pyramidal cells in the hippocampus, thereby reducing gamma waves (see SRF related news story). Edmund Rolls and associates (Rolls et al., 2008) suggest that reduced dopamine in schizophrenia decreases NMDA currents, causing neural networks to randomly fire, adding noise that drowns out information-carrying signals, rendering the networks unstable. Daniel Durstewitz and Jeremy Seamans (2008) propose that imbalanced activation of dopamine D1 and D2 receptors in the prefrontal cortex may result in excess noise and overly frail representations in memory. These theories could lead one to expect imprecise or unstable working memory in schizophrenia.

Yet, when Gold and colleagues looked at previous findings regarding working memory in schizophrenia, they found reason to doubt that schizophrenia causes faster-decaying or less accurate memories. Members of the research team, Wei Zhang and Steven Luck, both of the University of California at Davis, had recently devised a way to separately examine the number of representations in memory, the precision of those memories, and their stability over time. This provided an opportunity for the research group to test current theories of deficits in the working memory of individuals with schizophrenia.

The researchers’ approach involved a case-control design in which the researchers tested the working memory of 31 clinically stable patients who met criteria for schizophrenia or schizoaffective disorder. They compared them with 26 mentally healthy subjects who had no history of psychosis. Controls mirrored the patients in age, sex, ethnicity, and parental education. All participants were presented with three or four different colors on a computer screen. After a pause when the screen went blank, subjects were to indicate the color shown in a particular spot by selecting and clicking on it on a color wheel. Subjects who stored the color in memory and recalled it when tested should select colors similar to those actually shown. Those who did not would have to guess.

By examining the distribution of errors, Gold and colleagues determined the probability that subjects held an item in memory at test time and the precision of that representation. To check the stability of working memory representations, they tried both a one-second and a four-second delay. They reasoned that if patients with schizophrenia have unstable memories, they should perform worse than control subjects after a short delay.

A mixed bag
The results suggest that schizophrenia reduces working memory capacity, causing subjects with schizophrenia to store fewer items. Even so, patients recalled items that had been stored in memory with the same precision as healthy subjects. Furthermore, the length of delay made no difference in either the number of items recalled or the precision of recall for either group, contrary to expectations of less stable memories in schizophrenia. “In our view, the recent biological accounts discussed above are at odds with much of the behavioral literature, and clearly at odds with the data presented here,” write Gold and associates.

While Gold et al. acknowledge that a longer delay might bring out unseen differences between the two groups of subjects, they think that a four-second delay should be sufficient for detecting the disruptive working memory deficits expected in schizophrenia. They cannot explain why the working memory of subjects with schizophrenia would hold fewer items, although they note that neuroimaging studies point to the parietal cortex, perhaps in league with the prefrontal cortex, in setting capacity for visual working memory. They write, “Unfortunately, there is very little understanding of the origins of capacity limits in the basic cognitive neuroscience literature.”

All of the patients in the study were undergoing treatment with antipsychotic medication, including clozapine in 18 cases, suggesting that other treatments had failed them (see SRF related news story). This indicates that clozapine may boost the signal-to-noise ratio (see SRF related news story). Gold and colleagues warn that untreated patients in the early stages of schizophrenia might show a different pattern of deficits. They also caution that the results might not extend to other working memory tasks that activate different neural pathways and/or do not involve color judgments.

Despite these findings, or maybe because of them, Gold and colleagues see “a great need” for models that explain the actual working memory deficits seen in schizophrenia. Even so, they write, “these models must accurately capture the behavioral endpoint, which is characterized primarily by reductions in storage capacity and not by an instability of the working memory representations.”—Victoria L. Wilcox.

Gold and colleagues have provided an extremely elegant example of how a precisely controlled behavioral study can be used to directly test implications generated by neurobiological theories of cognitive impairment in schizophrenia. Further, they have provided novel and important data in schizophrenia that should cause us to re-examine theories about the mechanisms underling working memory impairments in this illness.

As noted by Gold, it has been hypothesized that altered GABAergic, glutamatergic, and/or dopaminergic inputs into reverberating and oscillatory networks in prefrontal or parietal cortex among individuals with schizophrenia should render such networks unstable and lead to less precise working memory representations that are particularly prone to decay (Lisman et al., 2008; Durstewitz and Seamans, 2008; Rolls et al., 2008; Lewis et al., 2008). However, Gold and colleagues have shown that working memory representations in schizophrenia (at least of color memory) are neither less precise nor show evidence of exceptionally rapid decay. Instead, individuals with schizophrenia showed clearly reduced working memory capacity.

These data contribute to a systemic body of work generated by Gold and colleagues, who have investigated the many aspects of working memory that could be impaired in schizophrenia. They have also shown that iconic decay is not increased in schizophrenia (Hahn et al., 2010), that feature binding is intact (Gold et al., 2003), and that certain aspects of attentional control over working memory are intact (Gold et al., 2006), though others are impaired (Fuller et al., 2006). However, working memory capacity has consistently been shown to be reduced in schizophrenia across numerous studies (Gold et al., 2006; van Raalten et al., 2008; Silver et al., 2003). If we take these results seriously (and we should), they require us to look closely at the neural mechanisms postulated to modulate capacity limitations in working memory in order to generate clues to the mechanisms that may be leading to reduced working memory capacity in schizophrenia.

The neural mechanisms leading to working memory capacity limitations are still very much an open source of debate. However, one influential theory is that the number of â€œitemsâ€ that can be maintained in working memory is limited by the number of gamma cycles (30-100 Hz) that can be embedded within a theta cycle (Lisman, 2010). Related to the idea that originally drove the design of the Gold study, Lisman and others have hypothesized that individual items within working memory are represented by oscillating neural populations with spike rates phase-locked in a gamma cycle. The oscillatory activity representing different items must be kept isolated, potentially by keeping gamma activity for different items out of phase with each other. One way to accomplish this would be to couple such gamma cycles into a lower frequency theta oscillation that can help regulate and separate activity associated with different items (as well as maintain information about order). Lisman and others have argued that capacity constraints of approximately four items in working memory (Cowan, 2001) thus reflect the number of gamma cycles that can be embedded in a theta cycle (approximately four) (Lisman, 2010; Wolters and Raffone, 2008).

Goldâ€™s results suggest that it may not be the maintenance of the individual gamma-oscillating neural populations representing individual items that is impaired in schizophrenia. Instead, it may be either the ability to establish such synchronous neural activity associated with a specific item, or the ability to couple a number of different gamma-oscillating sub-networks into a theta cycle. Interestingly, a growing number of studies have shown altered gamma activity during working memory in schizophrenia (Barr et al., 2010; Basar-Eroglu et al., 2007; Light et al., 2006; Kissler et al., 2000), as well as some evidence for altered theta activity (Haenschel et al., 2009). However, additional work is needed to specifically examine gamma-theta coupling in schizophrenia and its role in determining capacity limitations in this disease.

The type of network models of working memory put forth by Wang and colleagues suggest that the dynamics of excitatory and inhibitory inputs drive the number of independent â€œactivity bumpsâ€ (i.e., items) that can be maintained in a network (Compte et al., 2000). A related idea about the mechanisms driving capacity limitations and variations in these limits across individuals has been put forth by Klingberg and colleagues, who have argued that the dynamics of such lateral inhibitory mechanisms in parietal cortex limit memory capacity to be between two and seven items (Edin et al., 2009). However, they have also argued that such capacity limits can be overcome, at least temporarily, by excitatory inputs into parietal cortex from prefrontal cortex (Edin et al., 2009). They have suggested that this provides a mechanistic account of top-down control over working memory capacity by prefrontal cortex. As such, given the evidence for at least some types of abnormalities in top-down control of attention in schizophrenia (Fuller et al., 2006; Hahn et al., 2010), and evidence for altered connectivity between prefrontal and parietal regions (Barch and Csernansky, 2007; Karlsgodt et al., 2008), another possible source of reduced capacity in working memory in schizophrenia may be a reduction in prefrontal-mediated excitatory input into parietal networks that maintain items in working memory.

One might argue that the same GABA, glutamate, or dopamine mechanisms thought to impair the maintenance of representations in working memory could also impair the initial establishment of gamma oscillating networks representing items, their coupling to a lower-frequency theta cycle, or even the ability of prefrontal cortex to provide excitatory inputs into neural networks supporting the representation of items in working memory. If so, such models will also need to explain how such impairments could lead to reduced working memory capacity in schizophrenia without a change in precision or decay, a challenge for most current neural network models of working memory. As such, the data provided by Gold and colleagues suggest an exciting new pathway for research on working memory in schizophrenia that may allow us to develop more precise mechanistic hypotheses as to the source of these cognitive impairments and their relationship to pathophysiology of this illness.